US2025084153A1PendingUtilityA1

Methods of treating al amyloidosis

Assignee: PROTHENA BIOSCIENCES LTDPriority: Jan 29, 2021Filed: Jan 29, 2022Published: Mar 13, 2025

Est. expiryJan 29, 2041(~14.5 yrs left)· nominal 20-yr term from priority

Inventors:Gene Kinney Wagner Zago Radhika Tripuraneni Carol Karp

A61K 2039/505A61P 7/00C07K 2317/24C07K 16/18

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References

Claims

Abstract

Antibody formulations and methods useful for treatment of patients with AL amyloidosis.

Claims

exact text as granted — not AI-modified

What is claimed is:

1 . A method of treating a patient having AL amyloidosis, comprising:
(a) determining:
(i) the Mayo Stage of the patient&#39;s AL amyloidosis, or
(ii) the 6 minute walk test distance (6 MWD) and ejection fraction (EF) of the patient, or
(iii) the Mayo Stage and the EF of the patient; and
(b) selecting the patient for treatment with an antibody which competes for binding to human amyloid A peptide or human kappa or lambda light chain immunoglobulin with 2A4 (ATCC Accession Number PTA-9662) or 7D8 (ATCC Accession Number PTA-9468), or competes for binding to kappa light chain immunoglobulin with 11-1F4 (ATCC Accession Number PTA-105) if the patient:
(i) has Mayo Stage IV AL amyloidosis; or
(ii) has a 6 MWD≥30 meters and ≤550 meters; or
(iii) has a 6 MWD≥150 meters and an EF&gt;50% at baseline; or
(iv) has Mayo Stage IV and a 6 MWD≥30 meters and ≤550 meters; or
(v) has Mayo Stage IV and EF&gt;50% at baseline; or
(vi) has Mayo Stage IV, a 6 MWD≥150 meters and an EF&gt;50% at baseline; and
(c) administering an effective dosage of the antibody, wherein the patient has not previously received or does not concomitantly receive daratumumab.

2 . The method of claim 1 , wherein the patient has Mayo Stage IV amyloidosis.

3 . The method of claim 1 , wherein the patient has a 6 MWD≥150 meters and an EF&gt;50%.

4 . The method of claim 1 , wherein the patient has a 6 MWD≥30 meters and ≤550 meters.

5 . The method of claim 2 , wherein the patient has an EF&gt;50%.

6 . The method of claim 5 , wherein the patient has a 6 MWD≥150 meters.

7 . The method of claim 2 , wherein the patient has a 6 MWD≥30 meters and ≤550 meters.

8 . A method of treating a patient having AL amyloidosis, comprising administering an effective dosage of an antibody which competes for binding to human amyloid A peptide or human kappa or lambda light chain immunoglobulin with 2A4 (ATCC Accession Number PTA-9662) or 7D8 (ATCC Accession Number PTA-9468), or competes for binding to kappa light chain immunoglobulin with 11-1F4 (ATCC Accession Number PTA-105), wherein the patient has (a) Mayo Stage IV AL amyloidosis, (b) a 6 minute walk distance (6 MWD)≥30 meters and ≤550 meters, (c) a 6 MWD≥150 meters and EF&gt;50%, (d) Mayo Stage IV and an EF&gt;50%, (e) Mayo Stage IV and a 6 MWD≥30 meters and ≤550 meters, or (f) Mayo Stage IV and a 6 MWD≥150 meters and EF&gt;50% and (g) the patient has not previously received or does not concomitantly receive daratumumab.

9 . The method of claim 8 , wherein the patient has Mayo Stage IV AL amyloidosis.

10 . The method of claim 8 , wherein the patient has a 6 MWD≥150 meters and an EF&gt;50%.

11 . The method of claim 9 , wherein the patient has a 6 MWD≥150 meters and an EF&gt;50%.

12 . The method of claim 9 , wherein the patient has an EF&gt;50%.

13 . A method of treating a patient having Mayo Stage IV AL amyloidosis and having NYHA class III or NYHA class IV, the method comprising administering to the patient a therapeutically effective dosage of an antibody which competes for binding to human amyloid A peptide or human kappa or lambda light chain immunoglobulin with 2A4 (ATCC Accession Number PTA-9662) or 7D8 (ATCC Accession Number PTA-9468), or competes for binding to kappa light chain immunoglobulin with 11-1F4 (ATCC Accession Number PTA-105) amount, wherein the patient has not previously received or does not concomitantly receive daratumumab.

14 . The method of claim 13 , wherein the patient&#39;s NYHA class is reduced by at least two classes.

15 . The method of any one of claim 13 or 14 , wherein the patient&#39;s NYHA class is assessed nine or more months after treatment.

16 . A method of reducing the risk of mortality in a patient having Mayo Stage IV AL amyloidosis and having NYHA class III or NYHA class IV, the method comprising administering to the patient a therapeutically effective dosage of an antibody which competes for binding to human amyloid A peptide or human kappa or lambda light chain immunoglobulin with 2A4 (ATCC Accession Number PTA-9662) or 7D8 (ATCC Accession Number PTA-9468), or competes for binding to kappa light chain immunoglobulin with 11-1F4 (ATCC Accession Number PTA-105) amount, wherein the patient has not previously received or does not concomitantly receive daratumumab.

17 . The method of claim 16 , wherein the risk of mortality is all-cause mortality.

18 . The method of claim 16 , wherein the risk of mortality is cardiac mortality.

19 . The method of any one of claims 16 to 18 , wherein the risk of mortality is assessed nine or more months after treatment.

20 . The method of any one of claims 16-19 , wherein the risk of mortality is reduced by at least 15% as compared to the risk of mortality in a control population.

21 . A method of reducing the risk of hospitalization in a patient having Mayo Stage IV AL amyloidosis, the method comprising administering to the patient a therapeutically effective dosage of an antibody which competes for binding to human amyloid A peptide or human kappa or lambda light chain immunoglobulin with 2A4 (ATCC Accession Number PTA-9662) or 7D8 (ATCC Accession Number PTA-9468), or competes for binding to kappa light chain immunoglobulin with 11-1F4 (ATCC Accession Number PTA-105) amount, wherein the patient has not previously received or does not concomitantly receive daratumumab.

22 . The method of claim 21 , wherein the risk of hospitalization in the patient is reduced by at least 20% as compared to the risk of hospitalization in a control population.

23 . A method of increasing the number of days alive out of hospital (DAOH) in a patient Mayo Stage IV amyloidosis, the method comprising administering to the patient a therapeutically effective dosage of an antibody which competes for binding to human amyloid A peptide or human kappa or lambda light chain immunoglobulin with 2A4 (ATCC Accession Number PTA-9662) or 7D8 (ATCC Accession Number PTA-9468), or competes for binding to kappa light chain immunoglobulin with 11-1F4 (ATCC Accession Number PTA-105) amount, wherein the patient has not previously received or does not concomitantly receive daratumumab.

24 . The method of claim 23 , wherein the number of DAOH increases by at least 20 days after one month of treatment as compared to a control population.

25 . The method of claim 23 or 24 , wherein the number of DAOH increases by at least 100 days after six months of treatment as compared to DAOH in a control population.

26 . The method of any one of claims 23-25 , wherein the number of DAOH increases by at least 300 after twelve months of treatment as compared to DAOH in a control population.

27 . The method of any one of claims 23-26 , wherein the number of DAOH increases by at least 600 after 24 months of treatment as compared to DAOH in a control population.

28 . The method of any one of claims 23-27 , wherein the number of DAOH increases by at least 900 after 48 months of treatment as compared to DAOH in a control population.

29 . A method of reducing NTproBNP in a patient having Mayo Stage IV AL amyloidosis, the method comprising administering to the patient a therapeutically effective dosage of an antibody which competes for binding to human amyloid A peptide or human kappa or lambda light chain immunoglobulin with 2A4 (ATCC Accession Number PTA-9662) or 7D8 (ATCC Accession Number PTA-9468), or competes for binding to kappa light chain immunoglobulin with 11-1F4 (ATCC Accession Number PTA-105) amount, wherein the patient has not previously received or does not concomitantly receive daratumumab.

30 . The method of claim 29 , wherein NTproBNP is reduced by at least 31% from a baseline after 3 months of treatment.

31 . The method of claim 29 or 30 , wherein NTproBNP is reduced by at least 45% from a baseline after 3 months of treatment.

32 . The method of any one of claims 25-31 , wherein NTproBNP is reduced by at least 60% from a baseline after 3 months of treatment.

33 . The method of any one of claims 29-32 , wherein NTproBNP is reduced by at least 60% from a baseline to a nadir &gt;400 pg/ml after 3 months of treatment.

34 . The method of any one of claims 29-33 , wherein NTproBNP is reduced to a nadir &lt;400 pg/ml after 3 months of treatment.

35 . The method of any one of claims 29-34 , wherein NTproBNP is reduced by at least 45% from a baseline after 6 months of treatment.

36 . The method of any one of claims 29-35 , wherein NTproBNP is reduced by at least 60% from a baseline after 6 months of treatment.

37 . The method of any one of claims 29-36 , wherein NTproBNP is reduced by at least 60% from a baseline to a nadir &gt;400 pg/ml after 6 months of treatment.

38 . The method of any one of claims 29-37 , wherein NTproBNP is reduced to a nadir &lt;400 pg/ml after 3 months of treatment.

39 . A method of improving cardiac response rate in a patient having Mayo Stage IV AL amyloidosis, the method comprising administering a therapeutically effective amount of an antibody which competes for binding to human amyloid A peptide or human kappa or lambda light chain immunoglobulin with 2A4 (ATCC Accession Number PTA-9662) or 7D8 (ATCC Accession Number PTA-9468), or competes for binding to kappa light chain immunoglobulin with 11-1F4 (ATCC Accession Number PTA-105) amount, wherein the patient has not previously received or does not concomitantly receive daratumumab.

40 . The method of claim 39 , wherein the cardiac response rate increases at least 30% after 6 months of treatment as compared to baseline.

41 . The method of any claims 39 to 40 , wherein the cardiac response rate increases at least 50% after 12 months of treatment as compared to baseline.

42 . The method of any one of claims 39-41 , wherein the cardiac response rate increases at least 75% after 12 months of treatment as compared to baseline.

43 . A method of improving a six minute walk test (6 MWT) in a patient having Mayo Stage IV AL amyloidosis, the method comprising administering a therapeutically effective dosage of an antibody which competes for binding to human amyloid A peptide or human kappa or lambda light chain immunoglobulin with 2A4 (ATCC Accession Number PTA-9662) or 7D8 (ATCC Accession Number PTA-9468), or competes for binding to kappa light chain immunoglobulin with 11-1F4 (ATCC Accession Number PTA-105) amount, wherein the patient has not previously received or does not concomitantly receive daratumumab.

44 . The method of claim 43 , wherein the 6 MWT achieved is at least 300 meters.

45 . The method of claim 43 or 44 , wherein the 6 MWT achieved is at least 300 meters after treatment for 12 months.

46 . The method of any one of claims 43-45 , wherein the 6 MWT improves at least 33 meters as compared to baseline.

47 . The method of any one of claims 43-46 , wherein the 6 MWT improves at least 33 meters after 12 months of treatment as compared to baseline.

48 . The method of any one of claims 43-47 , wherein the 6 MWT achieved is at least 300 meters after treatment for 18 months.

49 . The method of any one of claims 43-47 , wherein the 6 MWT improves at least 33 meters after 18 months of treatment as compared to baseline.

50 . A method of increasing a Kansas City Cardiomyopatthy Questionnaire (KCCQ) score in a patient having Mayo Stage IV AL amyloidosis, the method comprising administering a therapeutically effective dosage of an antibody which competes for binding to human amyloid A peptide or human kappa or lambda light chain immunoglobulin with 2A4 (ATCC Accession Number PTA-9662) or 7D8 (ATCC Accession Number PTA-9468), or competes for binding to kappa light chain immunoglobulin with 11-1F4 (ATCC Accession Number PTA-105) amount, wherein the patient has not previously received or does not concomitantly receive daratumumab.

51 . The method of claim 50 , wherein the KCCQ score increased by at least 5 after 3 months of treatment as compared to baseline.

52 . The method of claim 50 or 51 , wherein the KCCQ score increased by at least 10 after 3 months of treatment as compared to baseline.

53 . The method of any one of claims 50-52 , wherein the KCCQ score increased by at least 15 after 3 months of treatment as compared to baseline.

54 . The method of any one of claims 50-53 , wherein the KCCQ score improves by at least 20 after 3 months of treatment as compared to baseline.

55 . The method of any one of claims 50-54 , wherein the KCCQ score improves by at least 5 after 12 months of treatment as compared to baseline.

56 . The method of any one of claims 50-55 , wherein the KCCQ score improves by at least 10 after 12 months of treatment as compared to baseline.

57 . The method of any one of claims 50-56 , wherein the KCCQ score improves by at least 15 after 12 months of treatment as compared to baseline.

58 . The method of any one of claims 50-57 , wherein the KCCQ score improves by at least 20 after 12 months of treatment as compared to baseline.

59 . A method of increasing Major Organ Deterioration Progression Free Survival in a patient having Mayo Class IV AL amyloidosis, the method comprising administering to the patient a therapeutically effective dosage of an antibody which competes for binding to human amyloid A peptide or human kappa or lambda light chain immunoglobulin with 2A4 (ATCC Accession Number PTA-9662) or 7D8 (ATCC Accession Number PTA-9468), or competes for binding to kappa light chain immunoglobulin with 11-1F4 (ATCC Accession Number PTA-105) amount, wherein the patient has not previously received or does not concomitantly receive daratumumab.

60 . The method of claim 59 , wherein NTproBNP is reduced by at least 31% from a baseline after 3 months of treatment.

61 . The method of claim 59 or 60 , wherein NTproBNP is reduced by at least 45% from a baseline after 3 months of treatment.

62 . The method of any one of claims 59-61 , wherein NTproBNP is reduced by at least 60% from a baseline after 3 months of treatment.

63 . The method of any one of claims 59-62 , wherein NTproBNP is reduced by at least 60% from a baseline to a nadir &gt;400 pg/ml after 3 months of treatment.

64 . The method of any one of claims 59-63 , wherein NTproBNP is reduced to a nadir &lt;400 pg/ml after 3 months of treatment.

65 . The method of any one of claims 59-63 , wherein NTproBNP is reduced by at least 45% from a baseline after 6 months of treatment.

66 . The method of any one of claims 59-65 , wherein NTproBNP is reduced by at least 60% from a baseline after 6 months of treatment.

67 . The method of any one of claims 59-66 , wherein NTproBNP is reduced by at least 60% from a baseline to a nadir &gt;400 pg/ml after 6 months of treatment.

68 . The method of any one of claims 59-67 , wherein NTproBNP is reduced to a nadir &lt;400 pg/ml after 3 months of treatment.

69 . The method of any of the preceding claims , wherein the antibody comprises a light chain variable region comprising three complementarity determining regions of 2A4, 7D8 or 11-1F4, and a heavy chain variable region comprising three complementarity determining regions of 2A4, 7D8 or 11-1F4, respectively.

70 . The method of any of the preceding claims , wherein the antibody is a humanized version of 2A4.

71 . The method of any of claims 1-70 , wherein the antibody is a humanized or chimeric version of 11-1F4.

72 . The method of any of claims 1-71 , wherein the antibody comprises a light chain variable region comprising three complementarity determining regions set forth as SEQ ID NOs: 3, 4 and 5, or SEQ ID NOs: 16, 17, and 18, and a heavy chain variable region comprising three complementarity determining regions set forth as SEQ ID NOs: 6, 7 and 8, or SEQ ID NOs: 19, 20, and 21.

73 . The method of any of claims 1-72 , wherein the light chain variable region comprises the amino acid sequence set forth as SEQ ID NO: 1 or 14.

74 . The method of any of claims 1-72 , wherein the heavy chain variable region comprises the amino acid sequence set forth as SEQ ID NO: 2 or 15.

75 . The method of any of claims 1-74 , wherein the light chain variable region comprises the amino acid sequence set forth as SEQ ID NO: 1 or 14, and the heavy chain variable region comprises the amino acid sequence set forth as SEQ ID NO: 2 or 15.

76 . The method of any of claims 1-75 , wherein the antibody comprises a light chain comprising the amino acid sequence set forth as SEQ ID NO: 10, and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 11, 12 or 13.

77 . The method of any of claims 1-76 , wherein the antibody comprises a light chain comprising the amino acid sequence set forth as SEQ ID NO: 10, and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 12.

78 . The method of any of claims 1-77 , wherein the antibody is birtamimab.

79 . The method of any of the preceding claims , wherein the patient is newly diagnosed and AL amyloidosis treatment naïve.

80 . The method of any of claims 1-72 , wherein the patient previously received or concomitantly receives treatment with melphalan, prednisone, dexamethasone, bortezomib, cyclophosphamide, lenalidomide, doxorubicin, doxycycline, autologous transplant, or a combination thereof.

81 . The method of any of claims 2, 5, 9, or 11 , comprising administering to the Mayo Stage IV patient an effective dosage of an antibody which competes for binding to human amyloid A peptide or human kappa or lambda light chain immunoglobulin with 2A4 (ATCC Accession Number PTA-9662) or 7D8 (ATCC Accession Number PTA-9468), or competes for binding to kappa light chain immunoglobulin with 11-1F4 (ATCC Accession Number PTA-105) and the patient has not previously received or concomitantly receives daratumumab, thereby reducing the patient&#39;s risk of mortality by at least about 35%.

82 . A method of treating a patient with AL amyloidosis, comprising:
a) determining that the patient has a 6 minute walk distance (6 MWD)≥30 meters and ≤550 meters or a 6 MWD≥150 meters and an ejection fraction (EF)&gt;50%; b) selecting the patient for treatment with an antibody which competes for binding to human amyloid A peptide or human kappa or lambda light chain immunoglobulin with 2A4 (ATCC Accession Number PTA-9662) or 7D8 (ATCC Accession Number PTA-9468), or competes for binding to kappa light chain immunoglobulin with 11-1F4 (ATCC Accession Number PTA-105); and c) administering an effective dosage of the antibody, wherein the patient has not previously received or does not concomitantly receive daratumumab.

83 . A method of treating a patient with AL amyloidosis who has a demonstrated 6 minute walk distance (6 MWD) of ≥30 meters and ≤550 meters or a 6 MWD greater than or equal to 150 meters and an ejection fraction (EF) of more than 50%, comprising administering to the patient an effective dosage of an antibody which competes for binding to human amyloid A peptide or human kappa or lambda light chain immunoglobulin with 2A4 (ATCC Accession Number PTA-9662) or 7D8 (ATCC Accession Number PTA-9468), or competes for binding to kappa light chain immunoglobulin with 11-1F4 (ATCC Accession Number PTA-105), wherein the patient has not previously received or does not concomitantly receive daratumumab.

84 . A method of reducing the risk of mortality in a patient with AL amyloidosis by at least 45%, comprising administering to the patient an effective dosage of an antibody which competes for binding to human amyloid A peptide or human kappa or lambda light chain immunoglobulin with 2A4 (ATCC Accession Number PTA-9662) or 7D8 (ATCC Accession Number PTA-9468), or competes for binding to kappa light chain immunoglobulin with 11-1F4 (ATCC Accession Number PTA-105), wherein the patient has Mayo Stage IV AL amyloidosis and/or has a demonstrated 6 minute walk distance (6 MWD)≥30 meters and ≤550 meters, or a 6 MWD of greater than or equal to 150 meters and an ejection fraction (EF) of more than 50%, or the patient has Mayo Stage IV AL amyloidosis and an EF of &gt;50%, wherein the patient has not previously received or does not concomitantly receive daratumumab.

85 . The method of claim 84 , wherein the risk of mortality is of all-cause mortality.

86 . The method of claim 85 , wherein the risk of all-cause mortality is reduced by at least about 48.9%.

87 . The method of claim 85 , wherein the risk of all-cause mortality is reduced by at least about 50%.

88 . The method of claim 85 , wherein the risk of all-cause mortality is reduced by at least about 50.2%.

89 . The method of claim 85 , wherein the risk of all-cause mortality is reduced by at least about 60%.

90 . The method of claim 85 , wherein the risk of all-cause mortality is reduced by at least about 70%.

91 . The method of claim 85 , wherein the risk of all-cause mortality is reduced by at least about 79.9%.

92 . The method of claim 85 , wherein the risk of all-cause mortality is reduced by at least about 81.5%.

93 . The method of claim 84 , wherein the risk of mortality is of cardiac mortality.

94 . The method of claim 93 , wherein the risk of cardiac mortality is reduced by at least about 75%.

95 . The method of 94 , wherein the risk of cardiac mortality is reduced by at least about 62.2%.

96 . The method of any of claims 81-95 , wherein the antibody is birtamimab.

97 . The method of any of the preceding claims , wherein the patient exhibits improvement in the 36-Item Short Form Survey Physical Component Score (SF-36 PCS) or SF-36v2 following treatment with the antibody.

98 . The method of claim 90 , wherein after nine months of treatment the change in the patient&#39;s score on the SF-36 PCS or SF-36v2 is at least 5 points higher relative to a different patient at the same time point who has not been administered the antibody.

99 . The method of any of the preceding claims , wherein the effective dosage of the antibody is administered from a pharmaceutical formulation comprising the antibody at a concentration within the range from about 1 mg/mL to about 100 mg/mL.

100 . The method of any of the preceding claims , wherein the dosage is from about 0.5 mg/kg to about 30 mg/kg and the antibody is administered intravenously or subcutaneously at a frequency of from about weekly to about quarterly.

101 . The method of claim 100 , wherein the antibody is present at a concentration of about 50 mg/mL.

102 . The method of any of claims 99-101 , wherein the dosage is administered intravenously following the transfer of an amount of the formulation required for the dosage from a vial to an intravenous bag containing a liquid.

103 . The method of any claims 99-102 , wherein the dosage is about 24 mg/kg and the antibody is administered intravenously every 28 days.

104 . The method of any of the preceding claims , wherein the duration of the treatment is at least 9 months.

105 . The method of claim 104 , wherein the duration of the treatment is at least 12 months.

106 . The method of any of the preceding claims , wherein the duration is effective to achieve or maintain at least about a 3 point increase from baseline in SF-36 PCS or SF-36v2.

107 . The method of any of the preceding claims , wherein the antibody is a Fab, Fab′, F(ab′) 2 , F(ab)c, Dab, nanobody, or Fv.

108 . The method of any of the preceding claims , wherein treatment results in a 20% relative reduction in hospitalization.

109 . The method of any of the preceding claims , wherein treatment results in a 310% to 60% reduction in NTproBNP from a baseline.

110 . The method of any of the preceding claims , wherein treatment results in a &gt;60% reduction in NTproBNP from a baseline to a nadir NTproBNP&gt;400 pg/mL.

111 . The method of any of the preceding claims , wherein treatment results in a nadir NTproBNP&lt;400 pg/mL.

112 . The method of any of the preceding claims , wherein treatment results in at least a 5 point change to a 20 point change in the Kansas City Cardiomyopathy Questionnaire (KCCQ) score.

113 . The method of any of the preceding claims , wherein after treatment of 12 months results in at least a 33 meter improvement in the 6 MWT.

114 . A method of improving a 6 minute walk distance (6 MWD) in a patient having AL amyloidosis, comprising administering to the patient an effective dosage of an antibody which competes for binding to human amyloid A peptide or human kappa or lambda light chain immunoglobulin with 2A4 (ATCC Accession Number PTA-9662) or 7D8 (ATCC Accession Number PTA-9468), or competes for binding to kappa light chain immunoglobulin with 11-1F4 (ATCC Accession Number PTA-105), wherein the patient has not previously received or does not concomitantly receive daratumumab.

115 . The method of claim 114 , wherein the AL amyloidosis is Mayo Stage IV AL amyloidosis.

116 . The method of claim 114 or 115 , wherein an ejection fraction (EF) of the patient is &gt;50%.

117 . The method of any of claims 114 to 116 , wherein the antibody in birtamimab.

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